The development of novel or improved dosage forms and delivery system for therapeutically active drugs has been and will continue to be the subject of research and development for both existing and novel drugs. More often, a particular delivery system delivers excessive amount of drug than is actually required, which leads to increased concentration of drug in blood plasma and is responsible for their respective side effects. The reasons for such theoretically excessive doses are many and include, inter alia, the mode of administration of the physiologically active ingredients.
The recent investigations with respect to transdermal or topical drug delivery system have increased resulting in a number of commercially viable products for the administration of various physiologically active anti-inflammatory agents with enhanced bioavailability and absorption. Diclofenac is one such anti-inflammatory and analgesic used widely in the pain management. Diclofenac and its pharmaceutically acceptable salts are presented most commonly in the form of tablets, injectables, gels and recently as clear aqueous solution for topical use. When orally administered diclofenac preparations are known to produce GI side effects. Research and development work has been conducted on topical dosage forms of diclofenac with a view of offering localized action at site of pain through various topical delivery systems.
Robert, S. M and Walker M (1993, In Pharmaceutical Skin Penetration Enhancement, 1-30) disclosed that the permeability of the pharmaceutical active ingredient is increased in presence of water due to hydration of the skin and solvation of the intercellular lipids. One of the proposed mechanisms for the facilitation of transport is by water being absorbed into the stratum corneum where it acts as a plasticizer in its bound state. In view of above theories, all topical preparations of diclofenac salts, like creams, gels, lotions and solutions is manufactured using water as an essential component with the objective of aiding permeation of the active drug.
The ex-vivo investigations by Minghetti, P. et.al. J. Pharm. Sci. 2007, April; 96(4):814-23 revealed that aqueous formulations containing diclofenac salt with an organic base appear to be the best combination to, promote permeation in topical applications. Wherein, the studies were carried out employing human skin for different diclofenac salts viz. sodium, potassium, diethylamine and epolamine and solvents viz. water, propylene glycol, oleic acid and transcutol.
In one another investigation, Nishihata, T. et al. Int. J. Pharm.; 1988; 46; 1-7 revealed that the rat dorsal percutaneous absorption of sodium diclofenac increased with an increase in sodium diclofenac concentration in an applied aqueous solution, but the bioavailability was poor. Further, the addition of 10% w/w ethanol in the aqueous solution containing sodium diclofenac apparently increased the percutaneous absorption of diclofenac and it was attributed to the increase in the sodium diclofenac concentration present in the applied solution. Further, the teachings by Ho Ho, et. al. J. Pharm. Pharmacol. 1994; 46; 636-42 disclosed that maximal penetration rate was found in a vehicle containing water and ethanol in a ratio of 3:1.
U.S. Pat. No. 4,353,896 describes a penetration of topical medicament useful in treating athletic injuries or other painful subdermal conditions. Wherein, the formulation is an aqueous based dosage form containing hydrocortisone, DMSO, methyl salicylate and alcohol.
U.S. Pat. No. 4,933,184 describes aqueous formulations containing menthol that produce enhanced transdermal drug delivery.
U.S. Pat. No. 4,652,557 describes pharmaceutical solutions containing active pharmaceutical ingredients, including diclofenac, in a solution comprising DMSO as penetration enhancer along with glycerol, propylene glycol and water.
U.S. Pat. No. 7,026,360 discloses pharmaceutical compositions containing non steroidal anti-inflammatory drugs including diclofenac with enhanced absorption of active ingredients. Phosphatidylcholine is used for the enhancement of absorption of active ingredients. The enhancement of absorption of active ingredient is sought by incorporation of 0.1% -20% by weight of phosphatidylcholine.
U.S. Pat. No. 5,093,133 teaches about the method for preparing hydro alcoholic gel of ibuprofen for percutaneous delivery. Wherein, the gel comprises ibuprofen along with alcohol, non-volatile solvent, gelling agents, sufficient base and water.
U.S. Pat. No. 5,318,960 and 5,985,860 describes a composition for transdermal delivery of pain relieving NSAID's like ibuprofen, methotrexate, capsaicin, diphenhydramine, methylnicotinate, indomethacin, ketoprofen, aspirin, diclofenac sodium, etc. and combinations thereof. The compositions are manufactured by mixing an appropriate amount of surfactant and co-solubilizer i.e. alcohol to establish a non-aqueous phase. There after, an appropriate amount of distilled water is slowly added to form a clear oil continuous solution.
U.S. Pat. No. 5,654,337 relates to a composition of pharmaceutically active substance including anti-inflammatory agent in a formulation, which is rapidly absorbed through the skin. The formulation comprises a polar lipid like lecithin, surfactant, water and urea with a pH of about 6-8.
U.S. Pat. No. 6,054,484 describes about the transparent aqueous solution of diclofenac sodium dissolved in a solvent mixture of a fatty acid dialkylolamide and water. The aqueous solution is claimed to have higher penetration.
U.S. Pat. No. 6,193,996 describes a pressure sensitive skin adhesive for transdermal delivery of diclofenac. The formulation incorporates effective amount of diclofenac or its pharmaceutically acceptable salts in the mixture of adhesives with penetration enhancer.
WO9857624 teaches about an invention relating to pharmaceutical preparation for topical application containing alcohol along with short chain n-alkylpyrolidone and at least one pyrolidone substituted with long chain alkyl radical with sufficient quantity of water.
U.S. Pat. No. 5,665,378 states the use of formulations containing capsaicin and pamabrom to alleviate pain. The aqueous formulations are used either as patches or in the form of creams.
U.S. Pat. No. 4,704,406 discloses a non-aqueous solution composition of arylalkanoic acid or its salts as sprayable liquids. This objective is achieved by using a two component carrier system comprising volatile and non-volatile solvents and wherein the concentration of the volatile solvents (ethanol, isopropyl alcohol and propanol) is high as compared to the non-volatile solvents. Accordingly, the ratio of volatile to the non-volatile solvent range is range of 1:1 to 20:1 by weight. The essential features of this invention are to provide the rapid cooling and film formation at the site of application, through fast evaporation of volatile solvent.
Diclofenac or its pharmaceutically acceptable salts and other NSAIDs produce their anti-inflammatory analgesic action through inhibition of prostaglandin synthesis. On the other hand, counter irritants like menthol and methyl salicylate produce the sensation of heat at the site of application due to the increased blood circulation in the tissue. Keeping in view the diverse mechanism of action of diclofenac and counter irritants, combination of diclofenac or its pharmaceutically acceptable salts with counter irritants have been also formulated in the form of creams, gels and aerosols to take advantage of the diverse mechanisms of action of diclofenac and counter irritants. This mechanism of action helps to alleviate the pain and inflammation. All these preparations of pharmaceutically acceptable salts of diclofenac with counter irritants reported in the prior arts incorporate water as an essential component of the formulation.
Further it is obvious from the prior art that every inventor has focused on achieving penetration enhancement through use of one or more penetration enhancers and presenting them in one or more of the above dosage forms viz. creams, gels, aerosols, lotion, emulsions, aqueous solutions and non-aqueous solutions. Unfortunately, none of the prior art discloses about the choice of desired dosage form suitable for the salt of diclofenac through topical delivery with enhanced penetration and bioavailability.
In most of the inventions, inventors has tried one or more of a dosage forms for a given transdermal composition, wherein, it is apparent that inventors are certain about the requirement of the nature of the dosage form needed for the enhanced transdermal penetration and hence he/she attempts to prepare one or more of the dosage forms for a single composition. Moreover, the inventions that have disclosed about multiple dosage forms for a single composition have not disclosed any evidence for their superiority among the dosage forms designed, by comparing those dosage forms with the market available products.
Amongst predominantly large number of the topical solutions with enhanced transdermal absorption disclosed in the prior art, a majority of topical solutions use water as one of the essential ingredient in the vehicle with the object of attaining higher transdermal penetration through hydration of the stratum corneum. More particularly, water is used for its solubilizing property. Typical creams are prepared by dissolving water soluble ingredients in the aqueous phase and the oil soluble ingredients in the oily phase. The two phases are mixed along with suitable surfactant to form a cream. In case of aqueous solutions, water is used along with other co solvents and surfactants to solublize the water-soluble ingredients of the formulation and also as a hydrating agent for the skin and in some cases water also helps to reduce the viscosity if the solution.
Further, the non-aqueous topical solutions disclosed in the U.S. Pat. No. 4,704,406 exclude water since the inherent nature of the formulations does not justify the use of water in the formulation. The main objectives of these patents are to provide the rapid cooling and quick film formation at the site of application through evaporation of the solution present in the disclosed sprayable topical solution.
Therefore, there exists a need to formulate a stable, non-toxic, low viscous, non-aqueous, non-greasy topical formulation of pharmaceutically acceptable salt of diclofenac with an enhanced penetration of diclofenac into the skin at the site of application of said topical formulation.